Nickel allergy diagnosis and desensitization

Nickel allergy diagnosis

Nickel allergy typically manifests itself through skin reactions, including atopic dermatitis. Clinicians can diagnose this condition in different ways, depending on the exposure path, which can be via contact with nickel-containing objects, water, or food. Let's go through some of the most common ways to diagnose nickel allergy.

Patch testing - One of the most common ways to identify contact allergy due to sensitization to a specific substance, with nickel being the most common positive patch test allergen. Different concentrations of nickel sulfate are used, for instance, 5% in Europe and half this amount in the US. Subjects who respond to this test usually tend to have strong reactions. As for any other diagnostic test, both false positive and false negative results can occur. In particular:

·      False-positive reactions with follicular irritative reactions to the patch test may occur without real sensitization.

·      False-negative reactions are also a possibility. However, when there is a strong suspicion that an individual is allergic to nickel, the clinician can repeat the test using 5% nickel chloride and substances that increase penetrance into the skin (e.g., DMSO). Alternatively, the clinician can scratch the skin before applying the patch.

Specific training helps make the interpretation of this test more accurate and distinguish nickel allergy from generic irritative reactions. This is particularly important for nickel allergy tests because different specialists (i.e., pediatricians, allergologists, general practitioners) use them. 

The lymphocyte proliferation test - This test assesses a delayed type of hypersensitivity reaction. To test if positive when an antigen interacts with an antigen-presenting cell in vitro, stimulating the proliferation of antigen-specific T cells. This test can only identify a generic nickel sensitivity.

Prick test - This test, which in adults is performed on the forearm, is also called puncture or scratch test. It checks for immediate allergic reactions to a specific substance, and clinicians usually use it to diagnose pollen, mold, pet dander, dust mites, and food allergies. A prick test helps connect contact urticaria with a nickel allergy.

Intradermic test - It involves the injection of a small amount of the suspected allergen under the skin's surface. It is another skin test that helps determine whether an individual is allergic to a specific allergen. This test is seldom used in clinical practice. However, it can provide some additional information in case of a borderline or unclear result from a patch test. Doubtful results can be either false-positive reactions or false-negative results where the intradermic test can help confirm a strong clinical suspicion of dermatitis due to nickel allergy. (M?ller, 1989) Clinicians who use this test with different titrations can also identify to which degree an individual is sensitive to nickel exposure. A patch test says nothing regarding the individual level of nickel sensitivity. (Meneghini and Angelini, 1979)

Nickel allergy diagnosis in children

It is common to test for food allergies those children younger than five years who are affected by moderate-to-severe atopic dermatitis. The latter is particularly the case for children with intractable AD, which does not heal with standard treatment and topical ointments. Children who experience a reaction immediately after ingesting a specific food should also be tested. (Boyce et al., 2011; De Bruin et al., 2013)

If suspecting an immediate reaction, testing may include both a skin prick test and allergen-specific serum IgE tests. However, the latter tests can only indicate whether sensitization to nickel exists. Any positive results must always be confirmed by a food challenge test.

Patch testing is considered safe in children, although caution is needed when assessing positive reactions. Some limitations include the small patch test surface and the fact that children could be hyperactive and cause a loss of patch test materials, especially younger children.

Low-nickel diet

In another post, I have already discussed some of the foods excluded from a nickel-free diet. The latter can be a valuable tool to confirm a diagnosis of nickel allergy. The table below summarizes the list of foods that are either allowed and not allowed in this kind of diet.

Low-nickel diet instructions

Permitted Foods

Meats (all, including poultry)

Fish (except herring, salmon, and shellfish)

Eggs

Milk and dairy products

Cereal products

Polished rice

Pasta

Baked goods (except whole grains)

Fresh fruits

Vegetables (small amounts): cauliflower, cabbage, broccoli, potatoes, carrots, beets, dill, eggplants, cucumber, mushrooms, parsley

Beverages: Coffee Wine, beer

Not Permitted Foods

Foods (especially acid) cooked in stainless steel utensils

Canned foods and beverages

Herrings, shellfish, salmon

Fats, margarine

Whole-grain flours

Baking powder

Cocoa, chocolate

Pineapples, strawberries, raspberries

Peanuts, almonds, hazelnuts

Gelatin, dried fruits (dates, figs, plums, pineapple, etc.), licorice

Legumes: peas, lentils, beans, soy protein powder, Vegetables: onions, tomatoes, rabe, spinach, cabbage, kale, lettuce, leeks, asparagus.

Tea

Vitamin and dietary supplements

Double-blind placebo-controlled nickel challenge test

The gold standard method to diagnose food allergy or intolerance is the elimination diet and the corresponding double-blind, placebo-controlled provocation test. A matter of discussion is how to structure an elimination diet and suitable doses for the provocation test.

A protocol for the double-blinded placebo-controlled nickel challenge (DBPCNC) test has been proposed and clearly described by Antico and Soana (2015). According to the latter, the test must be conducted in a day-hospital regimen using a series of noncumulative doses of 0.5, 1, 5, 10, and 20 mg of nickel sulfate hexahydrate, which are equivalent to, respectively, 0.11, 0.22, 1.11, 2.23, and 4.47 mg of elemental nickel. Three placebo capsules are randomly added to the sequence of the above doses, which increase from lowest to the maximum dose (for instance: 0.5 mg, placebo, 1 mg, 5 mg, placebo, 10 mg, placebo, and 20 mg). Individuals undergoing this test are supposed to take one capsule a day every morning after an overnight fast on an empty stomach for a maximum of eight days.

Patients then record all symptoms experienced after taking each capsule (dose), together with the time of occurrence, the intensity, and the duration of the reaction. Patients reporting symptoms undergo a medical check-up. A challenge test is positive when it causes a relapse or an exacerbation of clinical manifestations of nickel allergy after the ingestion of one of the above doses of nickel (but not after taking a placebo capsule. Common reactions to the provocation test include widespread itching and an increase of >60% of the skin map score.

There is no explicit agreement on the doses that can induce a positive response during a provocation test. In most studies, scientists used doses that exceed up to 10 times the nickel amount usually present in an average individual's diet. (Jensen et al., 2003; Nielsen et al., 1999; Uter et al., 2009; Thyssen et al., 2010; di Gioacchino et al., 2000; Tammaro et al., 2011; Ricciardi et al., 2014; Pizzutelli, 2011; Jensen et al., 2006)

The nickel challenge test has a high degree of specificity, which means it is highly likely to give negative results in healthy subjects and in a patient whose hand eczema or dermatitis is not due to nickel sensitization. (Antico and Soana, 1999; Jensen et al., 2003; Nielsen et al., 1999) A positive patch test can help further corroborate a positive result from a nickel challenge test. (Jensen et al., 2003;2006; Hindensen et al., 2001; Christensen et al., 1981)

Patients who suffer from idiopathic urticaria or another allergic-like, non-IgE-mediated dermatitis who reacted positively to a nickel patch test should start a low-nickel diet and confirm their nickel sensitivity via a DBPCNC. (Antico and Soana, 2015)

The most common symptoms of nickel allergy include a rash or bumps on the skin, itching, which, in some cases, may be severe, redness or changes in skin color, and dry patches of skin resembling a burn. In particular, atopic dermatitis is a common symptom among subjects with food allergy. While immediate skin reactions to food are well known, sometimes food allergy can also manifest itself via late eczematous reaction. In cases of the latter, no accurate laboratory testing is available to test the association with a food allergy, including allergy to nickel from food, as the pathophysiology of the latter is unclear. Therefore, DBPCFCs are the gold standard method for the diagnosis of late eczematous reactions. With the latter, it is crucial to extend the observation period to 48h. An elimination diet can continue for one month to a maximum of six weeks. (Werfel et al., 2007) The reason why suspect food allergies require confirmation via food challenge is that it is possible that AD symptoms simply improve coincidentally or due to the placebo effect. (Katta and Schlichte, 2014)

Desensitization from nickel allergy

Some patients with nickel allergy undergo chelating therapies via oral administration of a nickel chelating agent, such as disulfiram, to reduce symptoms. The latter treatment can benefit patients allergic to nickel with hand eczema (Fowler, 1992), although desensitization to the effects of nickel is also possible in some patients.

Since nickel sensitization is a hapten-specific immunological process, inducing immune tolerance to this metal is possible.

By feeding individuals who are sensitive to nickel with nickel sulfate, it is possible to induce oral tolerance to nickel. This option opens a new door in terms of new treatments of nickel allergy. (Sharma, 2007).

Desensitization therapies based on specific oral administration are known to be somewhat successful (Minelli et al., 2010), but their efficiency, outcome, and stability vary individually (Bonamonte et al., 2011; Tammaro et al., 2009).

A surveilled oral treatment with tiny little doses of nickel sulfate can induce specific immunotolerance, including symptom reduction or suppression (Cirla, 2011).

Nickel sulfate (5 mg/week for six weeks) significantly reduced the degree of contact allergy when administered to patients allergic to nickel (Sjovall et al., 1987). Patch test reactions confirmed the results at the beginning and the end of the desensitization therapy.

Minelli et al. (2010) showed that oral hyposensitization with increasing doses of nickel sulfate (0.3 ng to 3000 ng/week) combined with an elimination diet could induce either partial or total remission of symptoms after one year and four months. Of the 24 subjects enrolled in this study, 20 remained symptom-free after reintroducing nickel-containing foods in their diet. The term "nickel vaccination" is often used to identify commercial oral hyposensitizing treatments available in some countries. However, the efficacy of these treatments has yet to be ultimately proven. (Minelli, 2005)

In another study, Panzani et al. (1995) showed complete symptom disappearance after one year in 29 out of 30 allergic individuals treated with oral nickel sulfate (0.1 ng/day) and who had followed a low nickel diet for a particular time. The remaining patient benefit from a partial symptom reduction. These subjects also gained an increase of tolerance, as demonstrated by oral provocation tests. However, results from patch tests were unchanged in twenty participants, whereas five experienced a reduction of positivity, and the remaining five had a negative patch test result. Another author published similar results (Bagot et al., 1995).

The results of all these studies suggest that hyposensitization with oral nickel sulfate is a promising option for the treatment of nickel-allergic subjects.

Conclusions

It appears that nickel allergy can be diagnosed in different ways, although DBPCN followed by a nickel exclusion diet to confirm the results remains the gold standard. If symptoms disappear after a nickel-free diet, a desensitization therapy is appropriate. The latter has shown some advantages. It is essential to consider that a nickel-free diet excludes many foods recommended by official dietary recommendations, such as fish, nuts, whole grains, legumes, and others.

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